Because drug abuse is a chronic disease, characterized by long-term changes in behavior, this project is geared at elucidating persistent abnormalities in brain function induced by drugs of abuse, including opiates and stimulants. Our studies evaluated factors that modulate morphine withdrawal in the rat. During opiate withdrawal, the accelerated firing of locus coeruleus (LC) neurons has suggested a functional role of the LC. In slices from morphine dependent rats, LC firing rates were suppressed due to incomplete tolerance. Naloxone returned LC firing rates to control, but not supernormal rates demonstrating a need for activation of extrinsic pathways absent in the slice. This observation challenges the generally accepted concept that LC cells, themselves, initiate excitatory activity in withdrawal. However, other in vivo studies from our laboratory have provided evidence that the LC initiates increases in neuronal activity associated with opiate withdrawal. The microinjection of methylnaloxonium, a quaternary opioid antagonist, directly into the LC but not in the central amygdala or dorsal parabrachial nucleus of morphine-dependent rats increases cerebral glucose metabolism in the LC and its projections. The discrepancy between the in vitro and in vivo assays of LC activity suggests that LC activation in vivo is due to an amplification of neuronal firing via feedback circuits, which are absent in the slice preparation.